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Gene Therapy for Parkinson's Disease
Parkinson's Disease Parkinson's disease is a degenerative disorder which affects the central nervous system. It is characterized by the loss of dopamine producing neurons in the mid-brain and the accumulation of a protein called alpha-synuclein in Lewy bodies located within neurons. The current cause or causes of Parkinson's disease is unknown, although both environmental factors, such as exposure to pesticides, and genetic factors have been implicated. Symptoms are usually motor-related early on with brain function degeneration and dementia in patients in later stages of disease. Current treatments mainly treat symptoms and there are no known cures for the disease. The treatments used are dopamine agonists and levodopa. Dopamine agonists activate dopamine receptors in the absence of dopamine and are known to have some severe side effects and lose their efficacy after some time. Surgery and deep brain stimulation are also used when drugs become non-functional. Regardless of the treatment, eventually their effectivity lessens and the patient will succomb to the disease. 1,2 http://en.wikipedia.org/wiki/Parkinson's_disease Gene Therapy Strategies for Parkinson's Disease Both viral and non-viral methods for gene therapy of Parkinson's disease are being considered. Most clinical trials are using the viral strategy, but both will be reviewed. Viral methods for gene therapy make use of the virus's innate abiilty to insert genetic material into the genome. The viral vector contains the gene of interest and insertional capacity but lacks the components necessary for viral replication. The two most common viral vectors used are adenoviral and lentiviral vectors. The adenovirus genome is smaller restricting the size of gene that can be inserted, however, it has a very low rate of insertional mutagenesis making it the leading strategy in viral gene therapy. It is most commonly used because it is considered nonpathogenic to humans and they elicit only a mild immune response. One issue to take into consideration is that many people have been exposed to adenovirus serotype 2 and have pre-existing antibodies which will neutralize the virus. Adenoviral vectors show good uptake into neuronal cells and with more than 100 adenoviral serotypes to choose from it is possible to create adenoviral vectors with differing cell specificity by pseudotyping. The lentiviral vector can accomodate larger gene sizes, up to 18 kb, and may produce longer transgene expression. Lentiviral vectors are typically pseudotyped with vesicular stomatitis virus G. The pseudotyped envelope has a broader cell tropism which may allow for better uptake into neuronal cells. The main barrier to both these systems is crossing the blood-brain-barrier, which means current strategies involve direct infusion into the brain. There are several gene therapy strategies targeting the use of enzymes for dopamine synthesis rather than supplying dopamine itself utilizing adenoviral and lentiviral vectors for delivery . Dopamine is synthesized from tyrosine, first using the enzyme and limiting factor for dopamine syntheis tyrosine hyroxylase to produce L-dopa. Dopamine is then synthesized from L-dopa by the aromatic amino acid decarboxylase. Tyrosine hydroxylase requires a co-factor named tetradyrobiopterine, which requires GTP-cyclohydrolase-1 for synthesis. Dopamine is then transferred to dopamine receptors using the transporter vesicular monoamine transporter. Gene therapy using the enzymes for dopamine synthesis may be more efficacious than dopamine agonists because continous production rather than high-dose treatments would result in better diffusion of dopamine and lower chances of side effects. According to a review by Allen, Patricia J. et. al in 2013 there are six current gene therapy clinical trials. These trials are using the genes for glutamine decarboxylase, aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), guanosine triphosphate cyclohydrolase 1 (in conjunction with TH and AADC), Neurturin (CERE-120) and glial cell derived neurotrophic factor. All but one trial is using the adenoviral derived vector delivery and one is using the lentiviral derived vector delivery strategy. 1,2 References 1. Allen, P.J and Feigin. A. Gene Based Therapies in Parkinson's Disease. Neurotherapeutics. October 2013. http://link.springer.com/article/10.1007%2Fs13311-013-0233-2 2. Couen, Philippe G., et. al. Parkinson's Disease: Gene Therapies. Cold Spring Harbor Perspectives in Medicine. 2012. http://perspectivesmedicine.net/content/2/4/a009431.short